Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metallothioneins (MTs) are low-molecular weight, cysteine-rich, metal-binding proteins. Pretreatment of animals with Zn increases tissue MT concentrations, and protects against Cd-induced toxicity. However, Zn treatment produces many effects in addition to increasing MT. Therefore, MT-I and -II knock-out (MT-null) mice were used to determine the roles of MT in Cd-induced hepatotoxicity and nephrotoxicity, as well as in Zn-induced protection. MT-null mice were more sensitive to CdCl2 (25 mumol/kg i.p.) hepatotoxicity, as evidenced by 25-fold increases in serum alanine aminotransferase activity, compared to 12-fold increases in control mice. Zn pretreatment (200 mumol/kg s.c. x 2 days) increased hepatic MT 80 fold in control mice but not in MT-null mice, and prevented CdCl2 hepatotoxicity in control mice only. It is concluded that MT plays a critical role in Cd-induced hepatotoxicity. In contrast to CdCl2-induced hepatotoxicity, MT-null mice were equally susceptible as controls to the Cd-MT (CdMT) (0.1-0.4 mg Cd/kg i.v.) nephrotoxicity, as evidenced by similar increases in urinary protein (up to 30-fold) and glucose excretion (up to 60-fold), as well as similar extent of proximal tubular necrosis. Zn increased renal MT (28-fold) in control mice only; however, it protected against CdMT-induced renal injury in both control and MT-null mice. These findings suggest that MT plays less of a protective role in protecting against CdMT-induced nephrotoxicity than CdCl2-induced hepatotoxicity, and that Zn-induced protection against CdMT-induced nephrotoxicity does not appear to be mediated through MT.
...
PMID:Metallothionein plays less of a protective role in cadmium-metallothionein-induced nephrotoxicity than in cadmium chloride-induced hepatotoxicity. 878 54

The subchronic toxic effects of thiabendazole (TBZ) administered in the diet at levels of 0 (control), 0.8 and 1.6% for 13 wk to male and female ICR mice were investigated. Mean body weights of male mice fed 0.8 or 1.6% TBZ showed a significant decrease compared with controls, except for wk 3 and 8 for mice fed 0.8% TBZ. Red blood cell parameters in male mice of treated groups were significantly lower than controls. Biochemistry showed increased concentrations of GOT and GPT in male and female mice of the 1.6% TBZ groups. Relative spleen or liver weights were significantly increased in male and female mice of treated groups. Relative kidney weights of treated mice tended to be increased in comparison with controls. Histological findings showed a marked haemosiderosis and extramedullary haematopoiesis in the spleen of treated mice. In the liver, sinusoidal dilatation and enlargement of liver cells were found in treated mice. In the kidney, atrophy of tubules with peritubular fibrosis, cell infiltration and some tubular necrosis were found in treated mice. Slight hyperplasia was found in the urinary bladder of treated mice. The findings in the present study indicate that TBZ caused a slight anaemia and liver or kidney injury at both levels tested, under these conditions.
...
PMID:Subchronic toxicity of thiabendazole (TBZ) in ICR mice. 888 72

Dimethyl sulfoxide (DMSO) can protect the liver from injury produced by a variety of hepatotoxicants when administered prior to or concomitant with the toxicants. This protective action has previously been attributed to DMSO-induced inhibition of bioactivation of the compounds to toxic intermediates. In these studies, the ability of DMSO to provide protection when administered 10 hr after a toxicant was evaluated in several animal models of xenobiotic-induced liver and kidney injury. In the guinea pig model of halothane-associated hepatotoxicity, male outbred Hartley guinea pigs received 2 ml/kg DMSO 10 hr after an inhalation exposure to 1.0% halothane, 40% O2 for 4 hr. DMSO decreased the extent of liver necrosis as indicated by a threefold decrease in plasma alanine aminotransferase activity 48 hr after exposure and a reduction in the incidence and extent of zone 3 necrosis. These results do not appear to be due to alterations in halothane biotransformation since DMSO administered at 10 hr after halothane had no affect on plasma concentrations of the halothane metabolite tritluoroacetic acid or covalent binding by reactive halothane biotransformation intermediates to hepatic protein. In addition, administration of the structurally analogous biotransformation inhibitor diallyl sulfide at 10 hr after halothane also had no affect on biotransformation or covalent binding but provided no protection from liver injury. Hepatic glutathione concentrations in the guinea pigs 24 hr after halothane exposure were also unaffected by late treatment with DMSO. Further studies in male Sprague-Dawley rats demonstrated the ability of DMSO to decrease the hepatic injury resulting from oral administration of 1.0 ml/kg chloroform or 0.5 ml/kg bromobenzene when administered 10 hr after either toxicant. The chloroform-treated rats also developed renal tubular necrosis with large increases in plasma creatinine and urea nitrogen, which were completely ameliorated by DMSO. Elucidating the mechanism(s) of this protective action of late DMSO administration should provide insight into the cascade of events that lead to liver and kidney injury from toxicants and, hopefully, therapeutic modalities for individuals suffering from acute, progressing, xenobiotic-induced hepatitis.
...
PMID:Late dimethyl sulfoxide administration provides a protective action against chemically induced injury in both the liver and the kidney. 900 50

Acetaminophen (APAP) hepatotoxicity is due to its biotransformation to a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), that is capable of binding to cellular macromolecules. At least two forms of cytochrome P450, CYP2E1 and CYP1A2, have been implicated in this reaction in mice. To test the combined roles of CYP1A2 and CYP2E1 in an intact animal model, a double-null mouse line lacking functional expression of CYP1A2 and CYP2E1 was produced by cross-breeding Cyp1a2-/- mice with Cyp2e1-/- mice. Animals deficient in the expression of both P450s developed normally and exhibited no obvious phenotypic abnormalities. Comparison of the dose-response to APAP (200-1200 mg/kg) indicated that double-null animals were highly resistant to APAP-induced toxicity whereas the wild-type animals were sensitive. Administration of 600 to 800 mg/kg of this drug to male wild-type animals resulted in increased plasma concentrations of liver enzymes (alanine aminotransferase, sorbitol dehydrogenase), lipidosis, hepatic necrosis, and renal tubular necrosis. In contrast, when APAP of equivalent or higher dose was administered to the double-null mice, plasma levels of liver enzymes and liver histopathology were normal. However, administration of 1200 mg of APAP/kg to the double-null mice resulted in infrequent liver lipidosis and mild kidney lesions. Consistent with the protection from hepatotoxicity, the expected depletion of hepatic glutathione (GSH) content was significantly retarded and APAP covalent binding to hepatic cytosolic proteins was not detectable in the double-null mice. Likewise, in vitro activation of APAP by liver microsomes from the double-null mice was approximately one tenth of that in microsomes from wild-type mice. Thus, the protection against APAP toxicity afforded by deletion of both CYP2E1 and CYP1A2 likely reflects greatly diminished production of the toxic electrophile, NAPQI.
...
PMID:Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. 977 15

Conventional resuscitation of hypovolemia due to hemorrhage has consisted of aggressive fluid administration. Recent studies have suggested that surgical control of bleeding before fluid resuscitation might improve early survival. The effects of limited resuscitation on organ function have not been assessed in these studies. We developed a model of moderate intraperitoneal hemorrhage designed to evaluate long-term end-organ function after various resuscitation protocols. Male Sprague-Dawley rats underwent ketamine anesthesia, followed by placement of femoral artery and vein lines. Intraperitoneal hemorrhage was induced by division of distal branches of the ileocolic artery and vein. After 5 minutes of bleeding, the animals were randomized to one of three resuscitation groups: Group 1 received no fluid resuscitation before surgical control of the hemorrhage; Group 2 received 0.5 mL of lactated Ringer's solution (LR) every 5 minutes for a mean arterial pressure (MAP) of less than 80 mm Hg; Group 3 received 2.0 mL of LR every 5 minutes for a MAP of less than 80 mm Hg. In all three groups, after 20 minutes, the bleeding was surgically controlled. All rats were then resuscitated with LR to a MAP of 80 mm Hg. The intravascular lines were removed, and the rats were allowed to recover from anesthesia and were returned to animal holding. On the 7th day, survivors were sacrificed, and their blood was assayed for hematocrit and serum levels of bilirubin, alanine aminotransferase, urea nitrogen, and creatinine. Kidneys, lungs, and liver were harvested for microscopic examination. Survival was lower in Group 2 than in the other groups (90%, 60%, and 100%, respectively; P = 0.04), but all deaths occurred within 3 hours of hemorrhage and were due to either hypovolemia or anesthetic complications. No histologic abnormalities were identified in the livers of the animals that survived, but pulmonary atelectasis and mild-to-moderate renal tubular necrosis were identified uniformly. No histologic differences could be discerned between the groups. Hematocrit and indices of liver and renal function were similar in all groups, and no animal developed organ dysfunction. In this model of moderate uncontrolled intraperitoneal hemorrhage, the volume of fluid resuscitation, or the absence of resuscitation, had an inconsistent effect of 7-day survival and did not influence function or histologic appearance of the liver, lungs, or kidneys 7 days after hemorrhage.
...
PMID:Initial resuscitation volume in uncontrolled hemorrhage: effects on organ function. 1007 94

Reactive oxygen species (ROS) have been associated with many human diseases, and glutathione (GSH)-dependent processes are pivotal in limiting tissue damage. To test the hypothesis that Gr1(a1Neu) (Neu) mice, which do not express glutathione reductase (GR), would be more susceptible than are wild-type mice to ROS-mediated injury, we studied the effects of diquat, a redox cycling toxicant. Neu mice exhibited modest, dose- and time-dependent elevations in plasma alanine aminotransferase (ALT) activities, 126+/-36 U/l at 2 h after 5 micromol/kg of diquat, but no ALT elevations were observed in diquat-treated C3H/HeN mice for up to 6 h after 50 micromol/kg of diquat. Histology indicated little or no hepatic necrosis in diquat-treated mice of either strain, but substantial renal injury was observed in diquat-treated Neu mice, characterized by brush border sloughing in the proximal tubules by 1 h and tubular necrosis by 2 h after doses of 7.5 micromol/kg. Decreases in renal GSH levels were observed in the Neu mice by 2 h post dose (3.4+/-0.4 vs 0.2+/-0.0 micromol/g tissue at 0 and 50 micromol/kg, respectively), and increases in renal GSSG levels were observed in the Neu mice as early as 0.5 h after 7.5 micromol/kg (105.5+/-44.1 vs 27.9+/-4.8 nmol/g tissue). Blood urea nitrogen levels were elevated by 2 h in Neu mice after doses of 7.5 micromol/kg (Neu vs C3H, 32.8+/-4.1 vs 17.9+/-0.3 mg/dl). Diquat-induced renal injury in the GR-deficient Neu mice offers a useful model for studies of ROS-induced renal necrosis and of the contributions of GR in defense against oxidant-mediated injuries in vivo.
...
PMID:Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice. 1707 87

Acetaminophen (APAP) overdose is often fatal, leading to fulminant hepatic and renal tubular necrosis in humans and animals. We studied the effect of a nutrient mixture (NM) containing, among other nutrients, lysine, proline, ascorbic acid, N-acetyl cysteine, and green tea extract, which has previously been demonstrated to exhibit a broad spectrum of therapeutic properties on APAP-induced hepatic and renal damage in ICR (Imprinting Control Region) mice. Seven-week-old male ICR mice were divided into four groups (A-D) of five animals each. Groups A and C mice were fed a regular diet for 2 weeks, while groups B and D mice were supplemented with 0.5% NM (w/w) during that period. Groups A and B received saline i.p., while groups C and D received APAP (600 mg/kg) i.p. All animals were killed 24 h after APAP administration, serum was collected to assess the liver and kidney functions, and the livers and kidneys were excised for histology. Mean serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, BUN (Blood Urea Nitrogen), creatinine, and BUN/creatinine ratios were comparable in groups A and B, increased markedly in group C and significantly lower in group D compared with group C. APAP caused significant centrilobular necrosis and glomerular damage in unsupplemented animals, while NM prevented these alterations. The results indicate that NM has potential to protect against APAP-induced liver and kidney damage.
...
PMID:A nutrient mixture prevents acetaminophen hepatic and renal toxicity in ICR mice. 1865 Feb 54

The objective of the present study was to explore modification in toxico-pathological responses of rats toward aflatoxins in the presence of cypermethrin. A total of 120 adult male rats divided into six equal groups received AF and cypermethrin alone or in different combinations. AF was administered daily into rats with a stomach tube at dose rates of 0, 0.5 and 1.0mg/kg AFB1. Cypermthrin was administered in the feed at dose levels of 0 and 500mg/kg. Rats administered AF alone showed depression, decrease in feed intake, body weight and loose feces. Livers exhibited fatty change, necrosis, newly formed bile ducts and increased diameter of hepatocytes and their nuclei. Lesions in kidney included tubular necrosis and pink homogeneous tubular casts. Serum ALT and creatinine concentrations increased while those of total proteins, albumin, serum cholesterol and triglycerides decreased. Rats fed cypermethrin only had decreased feed intake and body weight. Hepatocytes showed fatty change and cellular necrosis. A concurrent administration of AF with cypermethrin indicated a potentiation of the AF toxicity reflected by increased severity of clinical signs, mortality of the rats and decreased body weights. Kidneys' relative weight also showed an equivocal interaction between the two toxicants. Other parameters studied did not show significant differences between the rats administered AF alone or concurrently with cypermethrin.
...
PMID:Toxico-pathological effects in rats induced by concurrent exposure to aflatoxin and cypermethrin. 1897 77

This study comprehensively describes the effects of various levels of food reduction on a wide range of toxicological parameters in dietary-optimized rats (fed with approximately 75% of ad libitum food consumption daily; 16 g and 22 g/day for females and males, respectively) that has been established as a nutritionally appropriate and well-controlled animal model in conducting toxicity studies. Toxicological parameters, including general condition, ophthalmology, clinical pathology and anatomic pathology, were examined in dietary-optimized Crl:CD(SD) female and male rats fed 16 g and 22 g/day (control), 12 g and 17 g/day (75% group), 8 g and 11 g/day (50% group), or 4 g and 6 g/day (25% group), respectively for 2 weeks. There was mortality and morbidity including reddish urine in 25% group females. The reddish urine was identified as "hemoglobinuria" that resulted from extra/intra-vascular hemolysis induced by severe food reduction. Hemoconcentration, decreased leukocytes and platelets, decreases in nutritional elements (serum glucose, protein, and lipids), increased aspartate aminotransferase and alanine aminotransferase, imbalanced electrolytes, and/or decreased urinary pH were observed in all restriction groups. Histopathologically remarkable changes included erythrophagocytosis in the spleen/liver and renal tubular necrosis with hyaline cast/droplets in 25% group; in addition to bone marrow depletion, lymphoid depletion in thymus/spleen/lymph node, and/or decreased secretion in the prostate/seminal vesicle in all restriction groups. Most of these changes were considered attributable to nutritional deficiency, dehydration, accelerated protein catabolism, stress and/or hemolysis secondary to severe food reduction. These results will enable toxicologists to help distinguish primary drug-induced effects from secondary changes associated with decreases in food consumption.
...
PMID:Effects of reduced food intake on toxicity study parameters in rats. 1904 75

Liver ischemia-reperfusion injury (IRI) causes acute kidney injury (AKI) in mice characterized by renal endothelial cell apoptosis, renal tubular necrosis, inflammation, and filamentous (F)-actin disruption. Since heat shock protein 27 (HSP27) protects against apoptosis, necrosis, and stabilizes F-actin, we questioned whether overexpression of human HSP27 (huHSP27 OE) in mice would attenuate AKI after liver IRI. Twenty-four hours after hepatic IRI, HSP27 wild-type (WT) mice developed acute liver and kidney injury with elevated plasma alanine aminotransferase and creatinine, a reduced glomerular filtration rate, and histological evidence of renal endothelial cell apoptosis and tubular injury (necrosis, vacuolization, and F-actin disruption). The huHSP27 OE mice, however, were significantly protected against both liver and kidney injury after hepatic IRI. The huHSP27 OE mice also showed less induction of several proinflammatory mRNAs (TNF-alpha, MIP-2, and keratinocyte-derived cytokine), neutrophil infiltration, and reduction in apoptosis (terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling assay and DNA laddering) in the kidney compared with the HSP27 WT mice. Moreover, the huHSP27 OE mice showed significantly less disruption of F-actin in renal proximal tubules and better preserved vascular endothelial cell integrity compared with the huHSP27 OE mice. Finally, the kidney plays a major role in the hepatoprotective effects of huHSP27 overexpression as the hepatoprotection was reduced or abolished in mice subjected to unilateral or bilateral nephrectomy, respectively. Our results show that overexpression of huHSP27 protects against hepatic injury and AKI associated with liver IRI in vivo. Harnessing the mechanisms of cytoprotection with renal HSP27 may lead to new therapies for the perioperative AKI and liver injury associated with liver IRI.
...
PMID:Human heat shock protein 27-overexpressing mice are protected against acute kidney injury after hepatic ischemia and reperfusion. 1965 12


<< Previous 1 2 3 Next >>

---